Overall nucleophilic acyl substitution is most simply represented as follows:

What does the term "nucleophilic
acyl substitution" imply ?

A nucleophile is
an electron rich species that will react with an electron poor species (Nu
in scheme).An acyl group is R-C=O (where R can be alkyl or
aryl).... note the acyl group in both the starting material and the product.
A substitution note that the leaving group (LG)
is replaced by the nucleophile (Nu).

There are two fundamental
events in a nucleophilic acyl substitution reaction:

formation of the new
s bond to the nucleophile, Nu.

breaking of the s bond
to the leaving group, LG.

Overall, these events are the same as those in a simple nucleophilic
substitution (chapter 8),
note the fundamental similarity in the two general processes.

The difference in nucleophilic
acyl substitution is that when the nucleophile adds to the electrophilic
C, it becomes tetrahedral and an intermediate forms, then the
leaving group departs as shown below:

Question:
In nucleophilic substitution (e.g. for alkyl halides) the nucleophile
cannot attack until the leaving group leaves, why is there a difference ?

Nucleophilic
Acyl Substitution : Reactive Systems

If either of the reaction
components are very reactive, for example the nucleophile (e.g. anionic
nucleophiles such as HO- etc.) or the electrophile, the carboxylic
acid derivative (e.g. acyl chlorides or acid anhydrides) then the reaction
can occur directly as shown below.
This is similar to what we have talked about previously for the reactions for
epoxides (Chapter
16) and aldehydes / ketones (Chapter
17) with stronger nucleophiles.

NUCLEOPHILIC ACYL SUBSTITUTION FOR REACTIVE SYSTEMS

Step 1:
The nucleophile adds to the electrophilic C in the polar carbonyl group,
electrons from the C=O move to the electronegative O creating the tetrahedral
intermediate.

Step 2:
The intermediate collapses, reforming the strong C=O bond results in the
loss of the leaving group, leading to the new carbonyl containing system.

Nucleophilic
Acyl Substitution : Less Reactive Systems

If the reaction components
are less reactive, for example the nucleophile (e.g. neutral nucleophiles
such as H2O or ROH etc.) or the electrophile, the carboxylic acid
derivative (e.g. esters or amides) then the reaction will be very slow
unless the reaction is promoted.

Activating the Nucleophile

If a base is used, then this can activate the nucleophile by deprotonating it,
creating the more nucleophilic anion (e.g. H2O to HO-,
or ROH to RO-). In this case we see the mechanism discussed
previously.

Activating the Electrophile

If an acid is used then this can activate the electrophile by protonating the
carbonyl thus making it more electrophilic. In this case we see the mechanism
shown below:

This is similar to what we
have talked about previously for the reactions epoxides (Chapter
16) and aldehydes / ketones (Chapter
17) with weaker nucleophiles.

NUCLEOPHILIC ACYL
SUBSTITUTION FOR LESS REACTIVE SYSTEMS

Step 1:
An acid / base reaction. Protonation of a lone pair on the O of the carbonyl
group, this creates a more electrophilic, cationic system.

Step 2:
The nucleophile attacks the electrophilic C of the carbonyl group causing
the p bond in the C=O to break and allows for neutralization of the
positive charge. This converts the sp2 C=O into the sp3
tetrahedral intermediate.

Step 3:
Electrons on the O are used to aid the loss of the leaving group (see
note below). This reforms the p
bond of the carbonyl group.

Step 4:
An acid/base reaction. Deprotonation reveals the carbonyl of the product
and regenerates the acid catalyst.

Note:
In some cases (especially esters and amides) the leaving group must also
be activated prior to being lost. This can also be achieved by protonation.
This adds a step to the process shown above.